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. 2012 Feb 28:3:29.
doi: 10.3389/fphar.2012.00029. eCollection 2012.

Regulation of sirtuin function by posttranslational modifications

Franziska Flick  1 , Bernhard Lüscher
Affiliations

Regulation of sirtuin function by posttranslational modifications

Franziska Flick et al. Front Pharmacol. .

Abstract

Sirtuins are homologs of the yeast silencing information regulator 2 protein, an NAD(+)-dependent (histone) deacetylase. In mammals seven different sirtuins, SIRT1-7, have been identified, which share a common catalytic core domain but possess distinct N- and C-terminal extensions. This core domain elicits NAD(+)-dependent deacetylase and in some cases also ADP-ribosyltransferase, demalonylase, and desuccinylase activities. Sirtuins have been implicated in key cellular processes, including cell survival, autophagy, apoptosis, gene transcription, DNA repair, stress response, and genome stability. In addition some sirtuins are associated with disease, including cancer and neurodegeneration. These findings suggest strongly that sirtuins are tightly controlled and potentially responsive to different signal transduction pathways. Here, we review the posttranslational regulation mechanisms of mammalian sirtuins and discuss their relevance regarding the physiological processes, with which the different sirtuins are associated. The available data suggest that the N- and C-terminal extensions are the targets of posttranslational modifications (PTM) that can affect the functions of sirtuins. Mechanistically this can be explained by the interaction of these extensions with the catalytic core domain, which appears to be controlled by PTM at least in some cases. In contrast little is known about PTM and regulation of the catalytic domain itself. Together these findings point to key regulatory roles of the N- and C-terminal extensions in controlling sirtuin functions, thus connecting these regulators to different signaling pathways.

Keywords: ADP-ribosylation; NAD+-dependent deacetylation; acetylation; methylation; phosphorylation; proteolytic cleavage; sumoylation.

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Figures

Figure 1
Figure 1
Lysines are targeted by multiple posttranslational modifications. Acetylation is a reversible PTM that is controlled by acetyltransferases and deacetylases. These enzymes transfer acetyl groups from acetyl-CoA to lysine residues with loss of the positive charge. Acetylated lysine residues provide docking sites for proteins that possess a Kac interaction domain, e.g., bromodomains. Lysines can also be modified by a number of additional PTMs as indicated. These modifications compete with each other, thus acetylation can potentially interfere with these other PTMs. The removal of acetyl groups is catalyzed by HDAC and sirtuin deacetylases. Sirtuins are NAD+-dependent enzymes that transfer the acetyl group onto ADP-ribose under release of nicotinamide. This results in the generation of O-acetyl-ADP-ribose, a molecule with second messenger properties.
Figure 2
Figure 2
Schematic overview of human sirtuins and their PTMs. The seven mammalian sirtuins are schematically indicated with the blue boxes depicting the sirtuin-typic catalytic core domain. The catalytic domains are flanked by distinct N- and C-terminal extensions (gray boxes). The numbers below indicate amino acid numbers for orientation. Two isoforms (IF) are shown for SIRT2 and SIRT5, respectively. The ESA (“essential for SIRT1 activity”) sequence of SIRT1 (see below) is indicated. PTMs, nuclear localization sequences, nuclear export sequences, and proteolytic cleavage sites are indicated. The precise amino acids modified by the different PTMs are given in Table 1.
Figure 3
Figure 3
Control of SIRT2 catalytic activity by the ESA motif and regulation by phosphorylation. Two CK2 phosphorylation sites lie within the essential for SIRT1 activity (ESA) sequence motif found in the C-terminal extension of SIRT1. These phosphorylation sites flank one of the two key residues of the ESA motif (indicated in red). CK2-mediated phosphorylation is proposed to enhance the interaction of ESA with the catalytic core, thereby increasing SIRT1 affinity for substrates and enhancing catalytic activity. The ESA motif competes with DBC1 binding, a negative regulator of SIRT1. Enhanced interaction of ESA with the core domain of SIRT2 in response to CK2 phosphorylation would prevent binding of DBC1 and thus abrogate its inhibitory effect.
Figure 4
Figure 4
Summary of the regulation of the catalytic activity of Sirtuins. Most of the currently known PTMs that target sirtuins are directed to the N- and C-terminal extensions. These extensions may control sirtuin function by interacting with the catalytic core domain or with each other. Additionally the extensions may control intermolecular interactions (not indicated). Different PTMs target the N- and C-terminal extensions, thereby possibly controlling either intra- or intermolecular interactions. The regulation of Zn2+ binding by nitrosylation is potentially a common regulatory mechanism of sirtuins. For more details see the text.
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References

    1. Afshar G., Murnane J. P. (1999). Characterization of a human gene with sequence homology to Saccharomyces cerevisiae SIR2. Gene 234, 161–16810.1016/S0378-1119(99)00162-6 - DOI - PubMed
    1. Ahuja N., Schwer B., Carobbio S., Waltregny D., North B. J., Castronovo V., Maechler P., Verdin E. (2007). Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J. Biol. Chem. 282, 33583–3359210.1074/jbc.M705488200 - DOI - PubMed
    1. Allfrey V. G., Mirsky A. E. (1964). Structural modifications of histones and their possible role in the regulation of RNA synthesis. Science 144, 559.10.1126/science.144.3618.559-c - DOI - PubMed
    1. Ashraf N., Zino S., Macintyre A., Kingsmore D., Payne A. P., George W. D., Shiels P. G. (2006). Altered sirtuin expression is associated with node-positive breast cancer. Br. J. Cancer 95, 1056–106110.1038/sj.bjc.6603384 - DOI - PMC - PubMed
    1. Back J. H., Rezvani H. R., Zhu Y., Guyonnet-Duperat V., Athar M., Ratner D., Kim A. L. (2011). Cancer cell survival following DNA damage-mediated premature senescence is regulated by mammalian target of rapamycin (mTOR)-dependent inhibition of sirtuin 1. J. Biol. Chem. 286, 19100–1910810.1074/jbc.M111.240598 - DOI - PMC - PubMed

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